Cellular forces : adhering, shaping, sensing and dividing

Life’s building block is a cell. Different cell types are differentiated by specific functional properties. A white blood cell, for instance, can get rid of bacteria and many muscle cells contract together for proper muscle function. Deformation and force exertion play important roles in these processes. Bacteria have to be physically engulfed by the white blood cell, and the muscle cell has to contract in the right way. In this research we measured how much force cells exert and simultaneously visualized specific proteins. A newly developed technique enabled the visualization of the nanometer-structure of cellular adhesions. We also examined the relationship between cellular shape and orientation of an intracellular network of protein (actin). We discovered that the signal of yet another protein (p130Cas) alters the mechanical behavior of the cell when the stiffness outside the cell changes. Finally, we also examined the structure of other proteins (tubulin and H2B) during cell division. In all these processes we measured how much force a cell exerts on its environment. The results provide important insights in the mechanical component of cellular function and their role in lifeBiological and Soft Matter Physic

Center of pressure motion after calf vibration is more random in fallers than non-fallers: Prospective study of older individuals

Aging is associated with changes in balance control and elderly take longer to adapt to changing sensory conditions, which may increase falls risk. Low amplitude calf muscle vibration stimulates local sensory afferents/receptors and affects sense of upright when applied in stance. It has been used to assess the extent the nervous system relies on calf muscle somatosensory information and to rapidly change/perturb part of the somatosensory information causing balance unsteadiness by addition and removal of the vibratory stimulus. This study assessed the effect of addition and removal of calf vibration on balance control (in the absence of vision) in elderly individuals (> 65 years, n = 99) who did (n = 41) or did not prospectively report falls (n = 58), and in a group of young individuals (18-25 years, n = 23). Participants stood barefoot and blindfolded on a force plate for 135 s. Vibrators (60 Hz, 1 mm) attached bilaterally over the triceps surae muscles were activated twice for 15 s; after 15 and 75 s (45 s for recovery). Balance measures were applied in a windowed (15 s epoch) manner to compare center-of-pressure (CoP) motion before, during and after removal of calf vibration between groups. In each epoch, CoP motion was quantified using linear measures, and non-linear measures to assess temporal structure of CoP motion [using recurrence quantification analysis (RQA) and detrended fluctuation analysis]. Mean CoP displacement during and after vibration did not differ between groups, which suggests that calf proprioception and/or weighting assigned by the nervous system to calf proprioception was similar for the young and both groups of older individuals. Overall, compared to the elderly, CoP motion of young was more predictable and persistent. Balance measures were not different between fallers and non-fallers before and during vibration. However, non-linear aspects of CoP motion of fallers and non-fallers differed after removal of vibration, when dynamic re-weighting is required. During this period fallers exhibited more random CoP motion, which could result from a reduced ability to control balance and/or a reduced ability to dynamically reweight proprioceptive information. These results show that non-linear measures of balance provide evidence for deficits in balance control in people who go on to fall in the following 12 months

Patient-relevant health outcomes for von Willebrand disease, platelet function disorders, and rare bleeding disorders:a Delphi study

Background: To assess patient value, it is essential to regularly measure health outcomes that matter to patients. It is currently unknown which health outcomes are important for patients with autosomal inherited bleeding disorders. Objectives: This study aimed to assess which health outcomes are important for patients with autosomal inherited bleeding disorders, consisting of von Willebrand disease, platelet function disorders, and rare bleeding disorders, as seen from the patients’, caregivers’, and healthcare professionals’ perspectives. Methods: Two panels, one consisting of patients and caregivers, and one consisting of healthcare professionals participated in a Delphi process. A list of 146 health outcomes was identified from the literature. During 3 rounds, both panels rated the importance of health outcomes on a 5-point Likert scale. A health outcome was considered important by a panel if it received a median score of 5 with an IQR of ≤1. Results: In total, 13 patients, 10 caregivers, and 19 healthcare professionals participated in the Delphi study. Both panels reached consensus on the importance of health outcomes related to bleeding episodes, life-threatening complications, and the intensity and impact of menstruation. Patients and caregivers additionally reached consensus on the importance of health outcomes related to menstruation and the impact of the bleeding disorder on their daily lives. Healthcare professionals reached consensus on the importance of health outcomes related to treatment, joint health, and pain. Conclusion: In this study, health outcomes were identified that should be considered when implementing value-based health care in the care of patients with autosomal inherited bleeding disorders.</p

On the evolution of decoys in plant immune systems

The Guard-Guardee model for plant immunity describes how resistance proteins (guards) in host cells monitor host target proteins (guardees) that are manipulated by pathogen effector proteins. A recently suggested extension of this model includes decoys, which are duplicated copies of guardee proteins, and which have the sole function to attract the effector and, when modified by the effector, trigger the plant immune response. Here we present a proof-of-principle model for the functioning of decoys in plant immunity, quantitatively developing this experimentally-derived concept. Our model links the basic cellular chemistry to the outcomes of pathogen infection and resulting fitness costs for the host. In particular, the model allows identification of conditions under which it is optimal for decoys to act as triggers for the plant immune response, and of conditions under which it is optimal for decoys to act as sinks that bind the pathogen effectors but do not trigger an immune response.Comment: 15 pages, 6 figure

CT-measured skeletal muscle mass used to assess frailty in patients with head and neck cancer

BACKGROUND: Skeletal muscle depletion or sarcopenia is related to multiple adverse clinical outcome. However, frailty questionnaires are currently applied in the daily practice to identify patients who are potentially (un)suitable for treatment but are time consuming and straining for patients and the clinician. Screening for sarcopenia in patients with head and neck cancer (HNC) could be a promising fast biomarker for frailty. Our objective was to quantify sarcopenia with pre-treatment low skeletal muscle mass from routinely obtained neck computed tomography scans at level of third cervical vertebra in patients diagnosed with HNC and evaluate its association with frailty. METHODS: A total of 112 HNC patients with Stages III and IV disease were included from a prospective databiobank. The amount of skeletal muscle mass was retrospectively defined using the skeletal muscle index (SMI). Correlation analysis between SMI and continuous frailty data and the observer agreement were analysed with Pearson's r correlation coefficients. Sarcopenia was present when SMI felt below previously published non-gender specific thresholds (<43.2 cm2 /m2 ). Frailty was evaluated by Geriatrics 8 (G8), Groningen Frailty Indicator, Timed Up and Go test, and Malnutrition Universal Screening Tool. A univariate and multivariate logistic regression analysis was performed for all patients and men separately to obtain odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: The cohort included 82 men (73%) and 30 women (27%), with a total mean age of 63 (±9) years. The observer agreement for cross-sectional measurements was excellent for both intra-observer variability (r = 0.99, P < 0.001) and inter-observer variability (r = 0.98, P < 0.001). SMI correlated best with G8 frailty score (r = 0.38, P < 0.001) and did not differ per gender. Sarcopenia was present in 54 (48%) patients, whereof 25 (46%) men and 29 (54%) women. Prevalence of frailty was between 5% and 54% depending on the used screening tool. The multivariate regression analysis for all patients and men separately isolated the G8 questionnaire as the only independent variable associated with sarcopenia (OR 0.76, 95% CI 0.66-0.89, P < 0.001 and OR 0.76, 95% CI 0.66-0.88, P < 0.001, respectively). CONCLUSIONS: This is the first study that demonstrates that sarcopenia is independently associated with frailty based on the G8 questionnaire in HNC patients. These results suggest that in the future, screening for sarcopenia on routinely obtained neck computed tomography scans may replace time consuming frailty questionnaires and help to select the (un)suitable patients for therapy, which is highly clinically relevant

Upper bounds for number of removed edges in the Erased Configuration Model

Models for generating simple graphs are important in the study of real-world complex networks. A well established example of such a model is the erased configuration model, where each node receives a number of half-edges that are connected to half-edges of other nodes at random, and then self-loops are removed and multiple edges are concatenated to make the graph simple. Although asymptotic results for many properties of this model, such as the limiting degree distribution, are known, the exact speed of convergence in terms of the graph sizes remains an open question. We provide a first answer by analyzing the size dependence of the average number of removed edges in the erased configuration model. By combining known upper bounds with a Tauberian Theorem we obtain upper bounds for the number of removed edges, in terms of the size of the graph. Remarkably, when the degree distribution follows a power-law, we observe three scaling regimes, depending on the power law exponent. Our results provide a strong theoretical basis for evaluating finite-size effects in networks

Influence of MRI Follow-Up on Treatment Decisions during Standard Concomitant and Adjuvant Chemotherapy in Patients with Glioblastoma:Is Less More?

MRI is the gold standard for treatment response assessments for glioblastoma. However, there is no consensus regarding the optimal interval for MRI follow-up during standard treatment. Moreover, a reliable assessment of treatment response is hindered by the occurrence of pseudoprogression. It is unknown if a radiological follow-up strategy at 2-3 month intervals actually benefits patients and how it influences clinical decision making about the continuation or discontinuation of treatment. This study assessed the consequences of scheduled follow-up scans post-chemoradiotherapy (post-CCRT), after three cycles of adjuvant chemotherapy [TMZ3/6], and after the completion of treatment [TMZ6/6]), and of unscheduled scans on treatment decisions during standard concomitant and adjuvant treatment in glioblastoma patients. Additionally, we evaluated how often follow-up scans resulted in diagnostic uncertainty (tumor progression versus pseudoprogression), and whether perfusion MRI improved clinical decision making. Scheduled follow-up scans during standard treatment in glioblastoma patients rarely resulted in an early termination of treatment (2.3% post-CCRT, 3.2% TMZ3/6, and 7.8% TMZ6/6), but introduced diagnostic uncertainty in 27.7% of cases. Unscheduled scans resulted in more major treatment consequences (30%; p &lt; 0.001). Perfusion MRI caused less diagnostic uncertainty ( p = 0.021) but did not influence treatment consequences ( p = 0.871). This study does not support the current pragmatic follow-up strategy and suggests a more tailored follow-up approach. </p

Focal Thyroid Incidentalomas on F-18-FDG PET/CT:A Systematic Review and Meta-Analysis on Prevalence, Risk of Malignancy and Inconclusive Fine Needle Aspiration

BackgroundThe rising demand for 18F-fluorodeoxyglucose positron emission tomography with computed tomography (18F-FDG PET/CT) has led to an increase of thyroid incidentalomas. Current guidelines are restricted in giving options to tailor diagnostics and to suit the individual patient.ObjectivesWe aimed at exploring the extent of potential overdiagnostics by performing a systematic review and meta-analysis of the literature on the prevalence, the risk of malignancy (ROM) and the risk of inconclusive FNAC (ROIF) of focal thyroid incidentalomas (FTI) on 18F-FDG PET/CT.Data SourcesA literature search in MEDLINE, Embase and Web of Science was performed to identify relevant studies.Study SelectionStudies providing information on the prevalence and/or ROM of FTI on 18F-FDG PET/CT in patients with no prior history of thyroid disease were selected by two authors independently. Sixty-one studies met the inclusion criteria.Data AnalysisA random effects meta-analysis on prevalence, ROM and ROIF with 95% confidence intervals (CIs) was performed. Heterogeneity and publication bias were tested. Risk of bias was assessed using the quality assessment of diagnostic accuracy studies (QUADAS-2) tool.Data SynthesisFifty studies were suitable for prevalence analysis. In total, 12,943 FTI were identified in 640,616 patients. The pooled prevalence was 2.22% (95% CI = 1.90% - 2.54%, I2 = 99%). 5151 FTI had cyto- or histopathology results available. The pooled ROM was 30.8% (95% CI = 28.1% - 33.4%, I2 = 57%). 1308 (83%) of malignant nodules were papillary thyroid carcinoma (PTC). The pooled ROIF was 20.8% (95% CI = 13.7% - 27.9%, I2 = 92%).LimitationsThe main limitations were the low to moderate methodological quality of the studies and the moderate to high heterogeneity of the results.ConclusionFTI are a common finding on 18F-FDG PET/CTs. Nodules are malignant in approximately one third of the cases, with the majority being PTC. Cytology results are non-diagnostic or indeterminate in one fifth of FNACs. These findings reveal the potential risk of overdiagnostics of FTI and emphasize that the workup of FTI should be performed within the context of the patient’s disease and that guidelines should adopt this patient tailored approach